Interventions for treating acute high altitude illness

Daniel Simancas‐Racines; Ingrid Arevalo‐Rodriguez; Dimelza Osorio; Juan VA Franco; Yihan Xu; Ricardo Hidalgo

doi:10.1002/14651858.CD009567.pub2

. 2018 Jun 30;2018(6):CD009567. doi: 10.1002/14651858.CD009567.pub2

Interventions for treating acute high altitude illness

Daniel Simancas‐Racines ^1,^✉, Ingrid Arevalo‐Rodriguez ^1,^2,³, Dimelza Osorio ¹, Juan VA Franco ⁴, Yihan Xu ⁵, Ricardo Hidalgo ¹

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6513207 PMID: 29959871

Abstract

Background

Acute high altitude illness is defined as a group of cerebral and pulmonary syndromes that can occur during travel to high altitudes. It is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Acute high altitude illness includes a wide spectrum of syndromes defined under the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' and 'high altitude pulmonary oedema'. There are several interventions available to treat this condition, both pharmacological and non‐pharmacological; however, there is a great uncertainty regarding their benefits and harms.

Objectives

To assess the clinical effectiveness, and safety of interventions (non‐pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness.

Search methods

We searched CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, CINAHL, Wanfang database and the World Health Organization International Clinical Trials Registry Platform for ongoing studies on 10 August 2017. We did not apply any language restriction.

Selection criteria

We included randomized controlled trials evaluating the effects of pharmacological and non‐pharmacological interventions for individuals suffering from acute high altitude illness: acute mountain sickness, high altitude pulmonary oedema or high altitude cerebral oedema.

Data collection and analysis

Two review authors independently assessed the eligibility of study reports, the risk of bias for each and performed the data extraction. We resolved disagreements through discussion with a third author. We assessed the quality of evidence with GRADE.

Main results

We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow‐up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows.

Non‐pharmacological interventions (3 studies, 124 participants)

All‐cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low‐quality evidence).

Pharmacological interventions (11 trials, 375 participants)

All‐cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) −1.15, 95% CI −2.56 to 0.27; 2 studies, 25 participants; low‐quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence).

Authors' conclusions

There is limited available evidence to determine the effects of non‐pharmacological and pharmacological interventions in treating acute high altitude illness. Low‐quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High‐quality research in this field is needed, since most trials were poorly conducted and reported.

Plain language summary

Treatments for high altitude (mountain) illness

Background

Acute high altitude illness, also known as acute mountain sickness, may present with a variety of symptoms. It is caused by the decreasing level of oxygen at increasingly high altitudes; and it can be experienced when reaching a high altitude when travelling, hiking or climbing mountains or other elevated areas. People going to altitudes over 4000 metres, females, people younger than mid‐adulthood , and people with a history of migraine are at greater risk of suffering from altitude sickness. The most common symptoms are headache, loss of appetite , insomnia, and nausea. However, severe forms can include confusion, difficulty walking, progressive cough, shortness of breath, and even death.

Review question

What are the benefits and risks of different treatments for people suffering from high altitude illness?

Study characteristics

We included 13 studies with a total of 468 participants. Most studies included participants with mild or moderate forms of mountain sickness, and only one study included the severe neurological (disorder of the nervous system) form. Follow‐up was usually less than one day. We also identified two ongoing studies.

Key results

We found studies evaluating the following interventions: simulated descent with a hyperbaric chamber (medical use of oxygen in a special chamber at greater than atmospheric pressure to increase the availability of oxygen in the body); oxygen; medicines: acetazolamide, dexamethasone, ibuprofen, paracetamol, gabapentin, sumatriptan, nitric oxide, and magnesium sulphate. None of the studies reported the effects of these interventions on all‐cause mortality. The report of complete relief from acute mountain sickness symptoms, and adverse events was infrequent. Studies related to simulated descent with the use of a hyperbaric chamber did not find additional benefits or harms related to this intervention (3 studies, 124 participants). In addition, studies related to administration of medicines found some benefits in terms of reduction of symptoms with the use of acetazolamide (2 studies, 25 participants), and dexamethasone (1 study, 35 participants), without an increase in side effects.

Quality of the evidence

The quality of the evidence we found was low, and thus our certainty in the findings is limited. There was insufficient information on how the studies were conducted, and in some cases there was evidence of tampering at some stages of the trials. Furthermore, the number of persons in each study was very small (< 30 participants), and therefore the results were not clear (imprecise). Some studies were not blinded (that is, participants knew what experimental treatment they were receiving), and this could have affected how the participants evaluated their own symptoms.

Summary of findings

Background

High altitude is arbitrarily classified as high (1500 to 3500 metres), very high (3500 to 5500 metres), and extreme (above 5500 metres) (Paralikar 2010). At high altitude there is a drop in barometric pressure, which causes a decrease in the partial pressure of oxygen. In most cases, this hypobaric hypoxia triggers physiological responses that help the individual tolerate and adapt to the low oxygen conditions. However in other cases there are abnormal responses, that in turn cause one of three forms of acute altitude illness: acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) (Luks 2017).

Acute high altitude illness is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Factors such as the rate of ascent, the absolute change in altitude and individual physiology are the primary determinants as to whether HAI will develop or not (Palmer 2010). People going to altitudes over 4000 metres, females, people younger than mid‐adulthood, and people with a history of migraine are at greater risk of suffering from altitude sickness (Bärtsch 2013; Canoui‐Poitrine 2014).

Description of the condition

High altitude illness (HAI)

The potential medical problems associated with a high altitude excursion are many, and terminology has sometimes confused their classification. For the purposes of this review, high altitude illness (HAI) is defined as a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (Luks 2014). This includes syndromes covered by the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' (HACE),and 'high altitude pulmonary oedema' (HAPE). The risk categories for acute mountain sickness are shown in Appendix 1 (Luks 2010; Luks 2014). HAI is considered as an important cause of mountain mortality (Windsor 2009).

Other medical problems that may be encountered at high altitudes include acute hypoxia, cerebrovascular syndromes, peripheral oedema, retinopathy, retinal haemorrhage, thromboembolism, sleep disorders and periodic breathing, high altitude pharyngitis and bronchitis, ultraviolet exposure and keratitis (snow blindness) and exacerbation of pre‐existing illness (CATMAT 2007; Palmer 2010; Schoene 2008); however these will not be considered in this review.

Acute mountain sickness (AMS) and high altitude cerebral oedema (HACE)

AMS is a neurological disorder characterized by headache, anorexia, nausea and sometimes vomiting, light‐headedness, insomnia, and fatigue or loss of energy (Palmer 2010). Headache is the most prevalent symptom (Luks 2017). In contrast, HACE is a potentially fatal neurologic disorder that is characterized by altered consciousness or ataxia (Imray 2010), or both. If left untreated, HACE can result in death subsequent to brain herniation (Bailey 2009). HACE is widely viewed as the end stage of AMS, and is normally preceded by symptoms of AMS (Basnyat 2003), which suggests that they result from a similar pathophysiologic process (Palmer 2010). Both syndromes are characterized by oedematous brain swelling, and intracranial hypertension (Luks 2017). The severity of AMS can be graded using the Lake Louise Questionnaire, Environmental Symptoms Questionnaire, or by the use of a simple analogue scale (Imray 2010).

The pathophysiology apparently involves an interaction of multiple physiological responses to hypoxia (ventilation, cerebral vasculature, autonomic nervous system and nociceptive thresholds), and anatomical factors such as the compensatory capacity for cerebrospinal fluid, and the capacity of venous outflow (Luks 2017).

High altitude pulmonary oedema (HAPE)

HAPE is a non‐cardiogenic pulmonary oedema (Smedley 2013). It is characterized by cough, progressive dyspnoea with exertion, and decreased exercise tolerance, generally developing within two to four days after arrival at high altitude (Hall 2011). HAPE is rare after one week of acclimatization at a particular altitude (Maggiorini 2010; Palmer 2010). Hypoxia is the trigger that results in a complex cascade of events leading to HAPE (Stream 2008). Essentially, HAPE is due to a "persistent imbalance between the forces that drive water into the airspace and the biologic mechanisms for its removal" (Scherrer 2010). The hallmark of this condition is hypoxic pulmonary hypertension, which may be mediated via at least three potential mechanisms: defective pulmonary nitric oxide synthesis; exaggerated endothelin‐1 synthesis; and exaggerated sympathetic activation (Scherrer 2010). A defect in alveolar transepithelial sodium transport has also been suggested (Scherrer 2010). An extensive review of pulmonary hypertension induced by high altitude is reported by Pasha 2010.

Epidemiology of acute high altitude illness (HAI)

It has been estimated that 25% of people at moderate altitude are affected by acute mountain sickness (AMS), and 50% to 85% of travellers at 4000 meters or more (Eide 2012). The incidence of high altitude cerebral oedema and high altitude pulmonary oedema is much lower than for AMS, with estimates in the range of 0.1% to 4.0% (Luks 2010). Rapid ascent, poor acclimatization, physical exertion at altitude, young age, and history of prior altitude illness are major risk factors to develop HAI (Eide 2012). Other risk factors are permanent residence lower than 900 metres; obesity (Ri‐Li 2003); and coronary heart disease (Dehnert 2010).

(See Appendix 2 for a glossary of medical terms.)

Description of the intervention

Interventions for treating HAI can be broadly classified as pharmacological and non‐pharmacological. Several consensus statements and guidelines have been published in this area. Some of them have been published by the Wilderness Medical Society (Luks 2014); the Committee to Advise on Tropical Medicine and Travel statement (CATMAT 2007); and the Centers for Disease Control and Prevention (CDC; CDC Yellow Book 2016).

A) Non‐pharmacological interventions

Descent (Hackett 2004)
Hyperbaric chamber (Bärtsch 1993; Kasic 1991; Keller 1995)
Portable pressure bag or Gamow bag (Austin 1998; Freeman 2004; Zafren 1998)
Breathing system designed to conserve oxygen supplies at high altitude (Pattinson 2005)
Positive airway pressure and other therapies (Koch 2009; Schoene 1985)

B) Pharmacological interventions

Oxygen (Hill 1909; Zafren 1996)
Carbonic anhydrase inhibitors: acetazolamide (Grissom 1992)
Glucocorticosteroids: dexamethasone (Ferrazzini 1987; Hackett 1988; Hackett 2004; Levine 1989; Wright 2008); medroxyprogesterone (Wright 2008)
Non‐steroidal anti‐inflammatory drugs (NSAIDs): ibuprofen (Broome 1994; Harris 2003); paracetamol (Harris 2003); and aspirin (Burtscher 2001)
Selective 5‐hydroxytryptamine (1) receptor agonist: sumatriptan (Utiger 2002)
Inhaled nitric oxide (Scherrer 1996; Schoene 2004)
Anticonvulsant drugs: gabapentin (Jafarian 2007a)
Diuretics: furosemide (Hultgren 1975)
Calcium channel blockers: nifedipine (Oelz 1989; Oelz 1992)
Non‐selective phosphodiesterase inhibitor (theophylline or aminophylline) (Fisher 2000)
Magnesium (Dumont 2004)

How the intervention might work

Both pharmacological and non‐pharmacological interventions are used to treat acute high altitude illness; however, immediate descent or evacuation to a lower altitude is lifesaving and the treatment of choice for patients with fully developed severe high altitude illness (Luks 2014). Treatments other than descent are considered when descent is not possible due to bad weather, terrain or other logistical factors.

Some of the ways the pharmacological and non‐pharmacological treatments might work are as follows.

A) Acute mountain sickness (AMS) and high altitude cerebral oedema (HACE)

Carbonic anhydrase inhibitors (acetazolamide, methazolamide) inhibit carbonic anhydrase in the kidneys, resulting in bicarbonaturia and metabolic acidosis. This results in hyperventilation in order to compensate through a respiratory alkalosis and thus this drug causes improvements in ventilation in order to respond more fully to hypoxic stimuli at altitude (Leaf 2007). Acetazolamide can also cause pulmonary vasodilation unrelated to carbonic anhydrase inhibition (Höhne 2007).
Steroids (dexamethasone and medroxyprogesterone): dexamethasone blocks hypoxia‐induced endothelial dysfunction (Murata 2004; Murata 2005); and medroxyprogesterone acts as a respiratory stimulant (Wright 2004).
Furosemide: this diuretic drug would reduce pulmonary extravascular fluid accumulation; however, diuretics have no role in high altitude pulmonary oedema (HAPE) treatment particularly because many HAPE patients have concurrent intravascular volume depletion (Luks 2010).
Non‐steroidal anti‐inflammatory drugs (NSAIDs) (ibuprofen, paracetamol, aspirin): a prostaglandin‐mediated increase in cerebral microvascular permeability may contribute to the pathophysiology of AMS, and treatment with prostaglandin synthetase inhibitors may reduce this response (CATMAT 2007).
Selective 5‐hydroxytryptamine (1) receptor agonists (sumatriptan) are selective cerebral vasoconstrictors (Jafarian 2007b).
Anticonvulsant drugs (gabapentin): gabapentin is an anticonvulsant drug with analgesic properties (Cheng 2006; Maneuf 2006).
Hyperbaric therapy (chambers, manual air pump, fabric pressure bags or Gamow bags) simulate descent and gives symptomatic improvement within a few hours as a temporary measure while awaiting descent (CATMAT 2007).

B) High altitude pulmonary oedema (HAPE)

Calcium channel blockers (e.g. nifedipine) reduce pulmonary vascular resistance (Hackett 1992).
Nitric oxide is an endothelium‐derived relaxing factor which attenuates the pulmonary vasoconstriction produced by hypoxia (Blitzer 1996; Scherrer 1996; Schoene 2004; Wang 2003).
Non‐selective phosphodiesterase inhibitor (theophylline or aminophylline): the antihypoxia and antioxidation effects of aminophylline may reduce periodic breathing, cerebral and pulmonary microvascular permeability (Yang 2007), and also pulmonary artery pressure (Wright 2008).
Positive airway pressure and other therapies: breathing against a positive expiratory pressure improves arterial oxygen saturation (Bärtsch 1992; Larson 1992; Schoene 1985).

(See Appendix 3 for reported adverse effects of the pharmacological interventions).

Why it is important to do this review

It is important to conduct this systematic review for a number of reasons. First, many people travel to recreational areas located at high altitude, and with rapidly increasing levels of world travel, this trend is increasing (CATMAT 2007). Second, there is considerable uncertainty about the true effectiveness of the many approaches to treating acute HAI (Adams 2004; Bärtsch 2004; CATMAT 2007; Elphick 2004), and their clinical effectiveness and safety must be assessed. This is especially important, considering that travellers may be falsely reassured that they will be safe going to high altitudes, as they believe they have an effective remedy in their rucksacks in case they get ill.

A systematic review, including a rigorous assessment of the risk of bias, of the most up‐to‐date evidence will help clinicians make informed decisions on the use of non‐pharmacological and pharmacological interventions for treating acute HAI.

Objectives

To assess the clinical effectiveness, and safety of interventions (non‐pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs) irrespective of publication status (trials may be unpublished or published as an article, an abstract or a letter). We applied no language and no country limitation. We did not apply restrictions with respect to periods of follow‐up. We excluded studies about chronic mountain sickness or Monge’s syndrome (Leissner 2009; León‐Velarde 2010; Monge 1942). We excluded quasi‐randomized studies, and prospective observational studies for evaluating clinical effectiveness.

Types of participants

We included trials involving people with high altitude Illness (acute mountain sickness/high altitude cerebral oedema, or high altitude pulmonary oedema, or both), with or without a history of high altitude Illness. We did not apply any restriction by age and gender.

Types of interventions

Interventions

A) Non‐pharmacological interventions

Descent
Hyperbaric chamber
Portable pressure bag or Gamow bag
Breathing system designed to conserve oxygen supplies at high altitude
Positive airway pressure

B) Pharmacological interventions

Oxygen
Carbonic anhydrase inhibitors (e.g. acetazolamide)
Glucocorticosteroids: dexamethasone and medroxyprogesterone
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and paracetamol: ibuprofen, aspirin and paracetamol
Selective 5‐hydroxytryptamine (1) receptor agonist: sumatriptan
Inhaled nitric oxide
Anticonvulsant drugs (e.g. gabapentin)
Diuretics (e.g. furosemide)
Calcium channel blockers: nifedipine
Magnesium

Comparisons

Placebo, monotherapy or any combination (non‐pharmacological plus pharmacological; pharmacological interventions).

Types of outcome measures

Primary outcomes

All‐cause mortality: we assessed this outcome through three approaches.
1. The number of deaths from any cause divided by the number of the participants in each group.
2. To determine how many deaths were caused by HAPE or HACE: the number of deaths from high altitude pulmonary oedema (HAPE) or high altitude cerebral oedema (HACE) divided by the number of participants in each group.
3. To determine how lethal HAPE or HACE were: the number of deaths by HAPE or HACE divided by the number of participants affected by HAPE or HACE in each group.
Complete relief of acute mountain sickness symptoms: defined as the complete absence of acute mountain sickness symptoms by the end of the study.

Secondary outcomes

Reduction in illness severity scores of acute mountain syndrome (headache, nausea, insomnia and dizziness; alone or in any combination) evaluated by the Lake Louise Questionnaire (Roach 1993), Environmental Symptoms Questionnaire (Sampson 1983), or any other validated scale. Because these different scales are not directly comparable, we analysed the results for each scale separately.
Adverse events
1. Adverse events: total adverse events and total serious adverse events. We defined adverse events as "any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment" (Nebeker 2004). Adverse drug reaction was defined as "a response to a drug which is noxious and uninitiated, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic functions" (Nebeker 2004).

(See Appendix 3 for commonly described adverse events of the pharmacological approaches).

Search methods for identification of studies

Electronic searches

We identified RCTs through literature searching with systematic and sensitive search strategies specifically designed to identify relevant trials without restrictions to language or publication status.    We searched the following databases for relevant trials.

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7)
MEDLINE (Ovid SP, 1966 to 10 August 2017)
Embase (www.embase.com, 1988 to 10 August 2017)
LILACS (BIREME interface, 1982 to 10 August 2017)
ISI Web of Science (1973 to 10 August 2017)
CINAHL (EBSCO host, 1982 to 10 August 2017)
Wanfang (Wanfangdata.com to 10 August 2017)

We developed a subject‐specific search strategy in MEDLINE, and used that as the basis for the search strategies in the other databases listed. Where appropriate, the search strategy was expanded with search terms for identifying RCTs. Our search strategies can be found in Appendix 4.

Searching other resources

We scanned the World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch) for ongoing and unpublished trials on 19 August 2017; (see Appendix 5).

We developed the search strategy in consultation with the Information Specialist.

We scanned the reference lists and citations of included trials and any relevant systematic reviews identified for further references to additional trials.

Where necessary we contacted trial authors for additional information (February and March 2018 ).

Data collection and analysis

Selection of studies

Two review authors (DSR and IAR) independently assessed each reference identified by the search against the inclusion criteria. We resolved any disagreements by discussion. We consulted a third author (DO) as an arbiter if we could not reach agreement. We retrieved text in full for those references which appeared to meet the inclusion criteria, for further independent assessment by the same three review authors.

Data extraction and management

We used a predefined form to extract data (Appendix 6). We extracted the following data: eligibility criteria; demographics (age, gender, and country); rate of ascent (metres/hour); final altitude reached (metres); Acute Mountain Syndrome scale; study design; history of high altitude illness (HAI); type of HAI; intervention; and outcomes. For eligible studies, four review authors in two groups (DSR‒IAR and DO‒YX) extracted the data using the form. We resolved discrepancies through discussion or, when required, we consulted a fifth author (RH). We entered data into Review Manager 5 (RevMan 5) software (Review Manager 2014), and checked for accuracy. When information regarding any of the above was unclear, we attempted to contact authors of the original reports to obtain further details.

Assessment of risk of bias in included studies

We used Cochrane’s tool for assessing risk of bias, a two‐part tool that addresses six specific domains: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective reporting; and other bias (Higgins 2011). The first part describes the risk of bias, the second part provides criteria for making judgements about the risk of bias from each of the six domains in the tool. Based on this tool, we implemented a 'Risk of bias' worksheet to be completed for included studies. We used bias definitions from Porta 2008 for coding the "Other sources of bias" domain. The risk of bias was assessed by four review authors in two groups (DSR‒IAR and DO‒YX). We resolved any disagreement through consultation with an additional author (RH or JVAF). We displayed the results by creating a 'Risk of bias' graph, and a 'Risk of bias' summary figure using Review Manager 5 software (Review Manager 2014). We present the risk of bias in the Results section. We also provide summary assessments of the risk of bias for each outcome within and across studies (see Characteristics of included studies and Risk of bias in included studies).

Measures of treatment effect

We reviewed the evidence separately for the different interventions. For the binary outcomes (all‐cause mortality, complete relief of AMS symptoms, and adverse events), we presented results as summary risk ratios with 95% confidence intervals (95% CI). For continuous outcomes (reduction in illness severity scores) we reported the results as standardized mean difference with 95% CI instead of a mean difference as planned in the published protocol. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Unit of analysis issues

The unit of analysis was the patient. We collected and analysed a single measurement for each outcome from each participant.

Dealing with missing data

In the case of missing data on participants or missing statistics (such as standard deviations (SD)) we planned to contact the trial authors. If unsuccessful, we planned to base our main analysis on the number reaching follow‐up, but we planned to perform a sensitivity analysis for worst and best case scenarios. For all outcomes we carried out analyses, as far as possible, on an intention‐to‐treat basis; that is we planned to include all participants randomized to each group in the analyses. The denominator for each outcome in each trial was the number randomized minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We planned to evaluate the extent of heterogeneity by visual inspection of the forest plot, and to use the I² statistic to quantify it (Higgins 2003; Higgins 2011), investigating possible causes of heterogeneity through subgroup analysis. If pre‐specified subgroup analyses did not explain the statistical heterogeneity, we planned to perform a sensitivity analysis in which small studies would be excluded. However, due to the scarcity of information we were not able to perform the subgroup analysis. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Assessment of reporting biases

Where we suspected reporting bias, we planned to contact study authors asking them to provide missing outcome data. When this was not possible, and the missing data were thought to introduce serious bias, we planned to explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. We also planned to assess whether the review was subject to publication bias by using a funnel plot to graphically illustrate variability between trials. If asymmetry was detected, we planned to explore causes other than publication bias. We planned to conduct a funnel plot if 10 or more RCTs were included in the review. However, due to the scarcity of information we were not able to perform these analyses. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Data synthesis

We planned to summarize the findings using both fixed‐effect and random‐effects models. In the presence of statistical heterogeneity, and an absence of small‐study effects, we expected the 95% CI from the random‐effects model to include the 95% CI from the fixed‐effect model. In this case, we planned to report only the data using the random‐effects model as it appropriately conveys heterogeneity. If a substantial difference was observed between both models, we planned to investigate this further as it can be due to an association between effect size and sample size. However, due to the scarcity of information we were not able to perform this analysis. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Subgroup analysis and investigation of heterogeneity

We anticipated clinical heterogeneity in the effect of the intervention and we intended to conduct the following subgroup analyses, if the data were available.

Final altitude (metres)
High altitude illness history
The state of pre‐acclimatization
The regular intake of medication
Pre‐existing disease

We planned to perform subgroup analysis only for primary outcomes. However, due to the scarcity of information, we were not able to perform this analysis. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

Sensitivity analysis

We planned to conduct a sensitivity analysis comparing the results using all trials as follows.

For those RCTs with high methodological quality (studies classified as having a 'low risk of bias' (Higgins 2011)), we planned to choose three core domains instead of all: generation of allocation sequence, incomplete outcome data, and selective reporting bias.
For dichotomous outcomes, we planned to conduct ‘best‐case’ and ‘worst‐case’ scenarios. The ‘best‐case’ scenario is that all participants with missing outcomes in the experimental intervention group had good outcomes and all those with missing outcomes in the control intervention group had poor outcomes; the ‘worst‐case’ scenario is the converse (Higgins 2011).

We also planned to evaluate the risk of attrition bias, as estimated by the percentage of participants lost to follow‐up. Those studies with a total attrition of more than 20% or where differences between the groups exceed 10%, or both, would be included in the review but excluded from the meta‐analysis trials. However, due to the scarcity of information we were not able to perform this analysis. This is a change from the protocol (Martí‐Carvajal 2012), and is explained in the Differences between protocol and review section.

'Summary of findings' tables and GRADE

We used the principles of the GRADE system to assess the quality of the body of evidence associated with specific outcomes (Guyatt 2008): all‐cause mortality, by high altitude pulmonary oedema (HAPE), or by high altitude cerebral oedema (HACE); complete relief of acute mountain syndrome (AMS) symptoms; reduction in illness severity scores; and adverse events (safety). We developed 'Summary of findings’ (SoF) tables using GRADE software (GRADEpro GDT) for the comparisons.

Non‐pharmacological interventions for treating acute high altitude illness (Table 1).
Pharmacological interventions for treating acute high altitude illness (Table 2).

Summary of findings for the main comparison. Non‐pharmacological interventions for treating acute high altitude illness.

Non‐pharmacological interventions for treating acute high altitude illness
Patient or population: people suffering from high altitude illness  Setting: Swiss‒Italian border, USA.  Intervention: hyperbaric chamber, simulated descent (193 millibars)  Comparison: supplementary oxygen, simulated descent (20 millibars)
Outcomes and intervention	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes and intervention	Risk with various interventions	Risk with non‐pharmacological interventions	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
All‐cause mortality	‐	‐	‐	‐	‐	Not reported
Complete relief of AMS symptoms	‐	‐	‐	‐	‐	Not reported
Reduction in symptom score severity at 12 hours (Clinical score: ranged from 0 to 11 (worse)) Intervention: Simulated descent of 193 millibars versus 20 millibars	The mean score in the control group was 3.1	The mean score in the intervention group was 2.5	0.6 points lower with intervention	64 (1 RCT)	⊕⊕⊝⊝  Low ¹
Adverse effects during treatment Intervention: Hyperbaric chamber/ 160 millibars versus supplementary oxygen	0 per 1000	0 per 1000	Nil	29  (1 RCT)	⊕⊕⊝⊝  Low¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; OR: Odds ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

Pharmacological interventions for treating acute high altitude illness
Patient or population: people suffering from high altitude illness  Setting: Alaska, borders between China, India and Pakistan, Iran, Nepal, Tibet, Swiss‒Italian border.  Intervention: pharmacological interventions (dexamethasone, acetazolamide, gabapentin)  Comparison: placebo
Outcomes		*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes		Risk with various interventions	Risk with pharmacological interventions	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
All‐cause mortality		‐	‐	‐	‐	‐	Not reported
Complete relief of AMS symptoms (12 to 16 hours after treatment) Scale used: Acute Mountain Sickness score (ranged from 0 to 9 (worse))	Dexamethasone versus placebo	0 per 1000	471 per 1000	No estimable	35  (1 RCT)	⊕⊕⊝⊝  Low ¹
Reduction in symptom score severity Time of measurement: 1 to 48 hours after treatment, end of treatment Scale of measurement: Self‐administered AMS questionnaires (ranged from 0 to 90 (worse)), AMS Symptom Questionnaire (ranged from 0 to 22 (worse)), Acute Mountain Sickness score (ranged from 0 to 9 (worse)), HAH Visual analogue score (VAS) (range no stated), Lake Louise Score (from 0 to 15 (worse)),	Acetazolamide versus placebo			Standardized Mean Difference 1.15 lower  (2.56 lower to 0.27 higher)	25  (2 RCTs)	⊕⊕⊝⊝  Low ²
	Dexamethasone versus placebo	Mean change from baseline: 0.4 units	Mean change from baseline: 4.1 units	Difference of 3.7 units (reported by trial authors)	35  (1 RCT)	⊕⊕⊕⊝  Moderate ³
	Gabapentin versus placebo	Mean VAS score: 4.75	Mean VAS score: 2.92	Not stated	24  (1 RCT)	⊕⊕⊝⊝  Low ⁴
	Magnesium versus placebo	Mean score: 10.3 units	Mean score: 9 units	Not stated	25  (1 RCT)	⊕⊕⊝⊝  Low ⁴
Adverse effects Time of measurement: 1 to 48 hours after treatment, end of treatment Scale of measurement:not stated	Acetazolamide versus placebo	No reported	0 per 1000	Not estimable	25  (1 RCT)	⊕⊕⊝⊝  Low ⁴
	Gabapentin versus placebo	0 per 1000	0 per 1000	Not stated	24  (1 RCT)	⊕⊕⊝⊝  Low ⁴
	Magnesium sulphate versus placebo	77 per 1000	750 per 1000	Not stated	25  (1 RCT)	⊕⊕⊝⊝  Low ⁴
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; OR: Odds ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

Risk categories Luks 2010	Description
Low	Individuals with no prior history of altitude illness and ascending to  ≤ 2800 m/ 9186 feet.
Low	Individuals taking ≥2 days to arrive at 2500 to 3000 m/ 8202 to 9842 feet  with subsequent increases in sleeping elevation < 500m by day/  1640 feet by day.
Moderate	Individuals with prior history of AMS and ascending to 2500 to 2800 m  (8202 to 9186 feet) in one day.
Moderate	No history of AMS and ascending to > 2800 m (9186 feet) in one day.
Moderate	All individuals ascending > 500 m/d (1640 feet) (increase in sleeping  elevation) at altitudes above 3000 m / 9842 feet.
High	History of AMS and ascending to ? 2800 m / 9186 feet in one day.
High	All individuals with a prior history of HAPE or HACE.
High	All individuals ascending to > 3500 m/ 11,482 feet in one day.
High	All individuals ascending >500 m/ 1640 feet /d increase in sleeping  elevation above > 3500 m/ 11,482 feet.
High	Very rapid ascents (e.g., Mt. Kilimanjaro).

Term	Definition
Anorexia	The lack or loss of appetite accompanied by an aversion to food and the inability to eat
Ataxia	Impairment of the ability to perform smoothly coordinated voluntary movements
Brian herniation	Protrusion of tissue, structure, or part of an organ through the bone, muscular tissue, or the membrane by which it is normally contained
Dyspnoea	Difficult or laboured breathing
Dizziness	An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness
Endothelium	A layer of epithelium that lines the heart, blood vessels (endothelium vascular), lymph vessels (endothelium lymphatic), and the serous cavities of the body
Fatigue	The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli
Hallucination	Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real
Headache	The symptom of pain in the cranial region
Hypoxia	A disorder characterized by a reduction of oxygen in the blood
Insomnia	Disorders characterized by impairment of the ability to initiate or maintain sleep
Lightheadedness	See dizziness
Nausea	An unpleasant sensation in the stomach usually accompanied by the urge to vomit
Pulmonary oedema	An unpleasant sensation in the stomach usually accompanied by the urge to vomit
Pulmonary alveoli	Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place
Seizures	Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells.Clinicalmanifestations include abnormal motor, sensory and psychic phenomena

Drug	Description and contraindications	Adverse events
Paracetamol	It is a non‐steroidal anti‐inflammatory drug	Paracetamol may cause liver damage
Acetazolamide	Acetazolamide, an inhibitor of the enzyme carbonic anhydrase.  Hypersensitivity to acetazolamide or any excipients in the formulation.  Since acetazolamide is a sulfonamide derivative, cross sensitivity between acetazolamide, sulfonamides and other sulfonamide  derivatives is possible. Acetazolamide therapy is contraindicated in situations in which sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland failure, and in hyperchloraemic acidosis. It is contraindicated in patients with cirrhosis because of the risk of development of hepatic encephalopathy	Adverse reactions, occurring most often early in therapy, include paraesthesias, particularly a “tingling” feeling in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alteration and gastrointestinal disturbances such as nausea, vomiting and diarrhoea; polyuria, and occasional instances of drowsiness and confusion
Aspirin	It is a non‐steroidal anti‐inflammatory drug.	Reye’s syndrome (a rare but serious illness).  Stomach bleeding
Dexamethasone	Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Glucocorticoids cause varied metabolic effects. In addition, they modify the body’s immune responses to diverse stimuli.  Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have sodium‐retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogues including dexamethasone are primarily used for their anti‐inflammatory effects in disorders of many organ systems.  Contraindicated in systemic fungal infections	Several adverse events (e.g. hyperglycaemia, fluid retention, hypokalaemic alkalosis, potassium loss, sodium retention)
Furosemide	It is potent diuretic. Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide	The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalaemia and hypochloraemic alkalosis, and are extensions of its diuretic action
Gabapentin	Gabapentin is an anticonvulsant. Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients	Somnolence, dizziness, ataxia, fatigue, and nystagmus
Ibuprofen	It is a nonsteroidal anti‐inflammatory drug (NSAID)	Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. It is a an NSAID, which may cause severe stomach bleeding
Magnesium	Magnesium should not be administered if there is renal impairment, marked myocardial disease or to comatose patients	The usual precautions for parenteral administration should be observed. Administer with caution if flushing and sweating occurs. Respiration and blood pressure should be carefully observed during and after administration of magnesium chloride injection
Medroxyprogesterone	It is a derivative of progesterone.  Contraindications: known or suspected pregnancy or as a diagnostic test for pregnancy, undiagnosed vaginal bleeding, known or suspected malignancy of breast, active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease, liver dysfunction or disease, known sensitivity to medroxyprogesterone acetate	Fluid retention, and several others related with the prolonged use
Methazolamide	Methazolamide is a potent inhibitor of carbonic anhydrase. Methazolamide therapy is contraindicated in situations in which sodium and/or potassium serum levels are depressed, in cases of marked kidney or liver disease or dysfunction, in adrenal gland failure,  and in hyperchloraemic acidosis. In patients with cirrhosis, use may precipitate the development of hepatic encephalopathy	Adverse reactions, occurring most often early in therapy, include paraesthesias, particularly a “tingling” feeling in the extremities; hearing dysfunction or tinnitus; fatigue; malaise; loss of appetite; taste alteration; gastrointestinal disturbances such as nausea, vomiting, and diarrhoea; polyuria; and occasional instances of drowsiness and confusion
Nifedipine	It is a calcium channel blocker. Nifedipine must not be used in cases of cardiogenic shock. It is contraindicated in patients with a known hypersensitivity to any component of the tablet	Headache, flushing/heat sensation, dizziness, fatigue/asthenia, nausea
Temazepam	It is a benzodiazepine hypnotic agent. It is contraindicated in women who are or may become pregnant	Drowsiness
Theophylline	Theophylline is classified as amethylxanthine. Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: active peptic ulcer disease, seizure disorders and cardiac arrhythmias (not including bradyarrhythmias)	Nausea, vomiting, headache, and insomnia

Report ID(if different to Study ID)	Report IDs of other reports of this study(e.g. duplicate publications, follow‐up studies)

Date form completed(dd/mm/yyyy)
Name/ID of person extracting data
Reference citation
Study author contact details
Publication type (e.g. full report, abstract, letter)
Notes:

Study Characteristics	Eligibility criteria (Insert inclusion criteria for each characteristic as defined in the Protocol)	Eligibility criteria met?			Location in text or source(pg & /fig/table/other)
Study Characteristics		Yes	No	Unclear	Location in text or source(pg & /fig/table/other)
Type of study	Randomized Controlled Trial
Participants	Were they people with HAI (AMS/HACE and HAPE, or both).
Types of intervention	Did one group receive A) Non‐pharmacological interventions Rest and oxygen Descent Hyperbaric chamber Portable pressure bag or Gamow bag Breathing system designed to conserve oxygen supplies at high altitude Positive airway pressure B) Pharmacological interventions Carbonic anhydrase inhibitors (e.g. acetazolamide) Glucocorticosteroids: dexamethasone and medroxyprogesterone Non‐steroidal anti‐inflammatory drugs (NSAIDs): ibuprofen, paracetamol and aspirin Selective 5‐hydroxytryptamine(1) receptor agonist: sumatriptan Inhaled nitric oxide Anticonvulsivant drugs (e.g. gabapentin) Diuretics (e.g. frusemide) Calcium channel blockers: nifedipine Magnesium
Types of comparison	Did the comparison group receive a Placebo, monotherapy or any combination (non‐pharmacological plus pharmacological; pharmacological interventions).
INCLUDE EXCLUDE
Reason for exclusion	DO NOT PROCEED IF STUDY IS EXCLUDED FROM REVIEW
Notes:

	Descriptions as stated in report/paper	Location in text or source(pg &/fig/table/other)
Country(where the study was conducted)
Design(e.g. parallel, cluster)
Was the study multicentre?(if yes, state No. of centres)
Funders of the trial
Duration of trial(state start date and end date of trial)
Duration of participation (from start of recruitment to last follow‐up)
Ethical approval needed/ obtained for study	Yes No Unclear
Notes:

	Description Include comparative information for each intervention or comparison group if available	Location in text or source(pg & /fig/table/other)
Population description (describe any risk factors, and criteria for diagnosing high‐altitude pulmonary edema )
Setting (from where were participants enrolled?)
Inclusion criteria
Exclusion criteria
Method of recruitment of participants(e.g. phone, mail, clinic patients)
Total no. randomized
Withdrawals and exclusions (if not provided below by outcome)
Age
Sex
Race/Ethnicity
Notes:

	Description as stated in report/paper	Location in text or source(pg & /fig/table/other)
Drug name
No. randomized to group (specify whether no. people or clusters)
Details of the drug/intervention (e.g. brand, look, taste)
Dosing regimen(e.g. dose, frequency, duration)
Mode of Delivery(e.g. oral)
Co‐interventions(any additional interventions given)
Notes:

	Description as stated in report/paper	Location in text or source(pg & /fig/table/other)
Comparison
Outcome
Subgroup
Time point  (specify from start or end of intervention)
Results
Any other results reported(e.g. odds ratio, risk difference, CI or P value)
No. missing participants
Reasons missing
No. participants moved from other group
Reasons moved
Unit of analysis(by individuals, cluster/groups or body parts)
Statistical methods used and appropriateness of these(e.g. adjustment for correlation)
Reanalysis required?(specify, e.g. correlation adjustment)	Yes No Unclear
Reanalysis possible?	Yes No Unclear
Reanalysed results
Notes:

Domain	Risk of bias			Support for judgement (include direct quotes where available with explanatory comments)	Location in text or source(pg & /fig/table/other)
Domain	Low risk	High risk	Unclear		Location in text or source(pg & /fig/table/other)
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)*Outcome group: HAPE symptoms and course duration*
Outcome group: Adverse events
Blinding of outcome assessment (detection bias) Outcome group: HAPE symptoms and course duration
Outcome group: Adverse events
Incomplete outcome data (attrition bias) Outcome group: HAPE symptoms and course duration (short term: 24hrs)
Outcome group: HAPE symptoms and course duration (long term: 2‐7 days)
Outcome group: Adverse events
Selective outcome reporting? (reporting bias)
Notes:

Correspondence required for further study information(from whom, what and when)
Any additional comments you would like to make about this study:

Lake Louise Score (0 to 16) Roach 1993
Headache	No headache (0) Mild headache (1) Moderate headache (2) Severe headache (3)
Gastrointestinal symptoms	None (0) Poor appetite or nausea (1) Moderate nausea &/or vomiting (2) Severe nausea &/or vomiting (3)
Fatigue &/or weakness	Not tired or weak (0)  Mild fatigue/ weakness (1)  Moderate fatigue/ weakness (2)  Severe fatigue/ weakness (3)
Dizziness/lightheadedness	Not dizzy (0) Mild dizziness (1) Moderate dizziness (2) Severe dizziness, incapacitating (3)

	Description as stated in report/paper	Location in text or source(pg & /fig/table/other)
Comparison name
No. randomized to group (specify whether no. people or clusters)
Details of placebo(e.g. similarity to intervention)
Dosing regimen(e.g. dose, frequency, duration)
Mode of Delivery(e.g. oral)
Co‐interventions(any additional interventions given)
Notes:

	Description as stated in report/paper	Location in text or source(pg & /fig/table/other)
Outcome name	All‐cause mortality: The number of deaths from any cause divided by the number of the participants in each group. The number of deaths from HAPE or HACE divided by the number of participants in each group. To determine how many deaths were caused by HAPE or HACE. The number of deaths by HAPE or HACE divided by the number of participants affected by HAPE or HACE in each group. To determine how lethal were HAPE or HACE.
Time points measured (specify whether from start or end of intervention)
Time points reported
Person measuring/ reporting
How was pain assessed?(measurement scale)
Scales: upper and lower limits(indicate whether high or low score is good)
Is outcome/tool validated?	Yes No Unclear
Imputation of missing data  (e.g. assumptions made for ITT analysis)
Notes:

Clusters	A group of participants who have been allocated to the same intervention arm together, as in a cluster‐randomized trial, e.g. a whole family, town, school or patients in a clinic may be allocated to the same intervention rather than separately allocating each individual to different arms.
Co‐morbidities	The presence of one or more diseases or conditions other than those of primary interest. In a study looking at treatment for one disease or condition, some of the individuals may have other diseases or conditions that could affect their outcomes.
Compliance	Participant behaviour that abides by the recommendations of a doctor, other health care provider or study investigator (also called adherence or concordance).
Exclusions	Participants who were excluded from the study or the analysis by the investigators.
Imputation	Assuming a reasonable value for a measure where the true value is not available (e.g. assuming last observation carried forward for missing participants).
Reanalysis	Additional analysis of a study's results by a review author (e.g. to introduce adjustment for correlation that was not done by the study authors).
Report ID	A unique ID code given to a publication or other report of a study by the review author (e.g. first author's name and year of publication). If a study has more than one report (e.g. multiple publications or additional unpublished data) a separate Report ID can be allocated to each to help review authors keep track of the source of extracted data.
Sociodemographics	Social and demographic information about a study or its participants, including economic and cultural information, location, age, gender, ethnicity, etc.
Study ID	A unique ID code given to an included or excluded study by the review author (e.g. first author's name and year of publication from the main report of the study). Although a study may have multiple reports or references, it should have one single Study ID to help review authors keep track of all the different sources of information for a study.
Unit of allocation	The unit allocated to an intervention arm. In most studies individual participants will be allocated, but in others it may be individual body parts (e.g. different teeth or joints may be allocated separately) or clusters of multiple people.
Unit of analysis	The unit used to calculate N in an analysis, and for which the result is reported. This may be the number of individual people, or the number of body parts or clusters of people in the study.
Unit of measurement	The unit in which an outcome is measured, e.g. height may be measured in cm or inches; depression may be measured using points on a particular scale.
Validated	A process to test and establish that a particular measurement tool or scale is a good measure of that outcome.
Withdrawals	Participants who voluntarily withdrew from participation in a study before the completion of outcome measurement.

Methods	Two‐group parallel RCT, 1 centre ITT: no  Overall study quality: high risk of bias Unit of randomization: assignment of gas composition was randomized in blocks of 9 Follow‐up period: 24 h "all investigations were carried out within a day after arrival at 4559 m" Diagnosis of AMS Acute mountain sickness (AMS) score. “A score of more than 3 was required for entry to the trial” Scale used for assessing AMS Subscore (AMS‐C) including 11 statements (Appendix 8) Environmental symptom questionnaire (Appendix 8)
Participants	Number of participants randomized: 20 Sex: men = 19 (95%) Age: median 32 years (range 22 to 51) Baseline data Not reported Inclusion criteria Patients with an AMS score more than 3 Exclusion criteria Not clearly reported
Interventions	Intervention group 1 (n = 6) Oxygen in nitrogen. Dose: 33% (1.6%); route: breathing through a tightly fitted face mask; duration: 30 min; frequency: not clearly reported, apparently a single dose Intervention group 2 (n = 7) Carbon dioxide in air. Dose 3% (0.15%); breathing through a tightly fitted face mask; duration: 30 min; frequency: not clearly reported, apparently a single dose Control group (n = 7) Compressed "normal" air. Duration: 30 min; frequency: not clearly reported, apparently a single dose Co‐intervention Room air was provided for 30 min right before the experimental gas. The gas was humidified and the flow adjusted manually to the ventilation of the subject by the maintenance of a 50 litre reservoir‐balloon at a constant size
Outcomes	Not pre‐fixed as 'primary' or 'secondary' Severity of AMS (AMS‐C score, Appendix 8). Before and immediately after the treatment Symptoms of environmental stress (Appendix 8). After each clinical examination Physiological variables: ventilation, PaCO₂, PaO₂, Oxygen saturation Mean blood flow velocity in the median cerebral artery (MCA) Outcomes of interest in the review Reduction in illness severity scores of AMS
Notes	Country: Swiss‒Italian border, Capanna "Regina Margherita" in the Alps Valais Altitude setting: 4559 m (barometric pressure 430 mmHg to 440 mmHg) Study dates: not reported Identifier number: not reported A priori sample estimation: no Conflicts of interest: not reported Funding/Support "This study was supported by grant 3200‐0092.85 from the Swiss National Science Foundation"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "assignment of gas composition was randomised in blocks of nine" (page 773)
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk'
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "the person responsible for the gas supply, the gas bottles, and the reservoir‐balloon were hidden behind a curtain from the subjects and the examiners" (page 773)
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "four investigators carried out one each of four different measurements throughout the study‐clinical examinations, ventilation, blood gas analysis, and transcranial doppler ultrasound examination. They were not aware of each other’s results during treatment of any particular patient" (page 773)
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All outcomes: no withdrawals. Outcome data was available for all participants
Selective reporting (reporting bias)	High risk	Results are reported in a figure. Exact numbers could not be retrieved. In the text, authors reported interpretation of data and P values
Other bias	Unclear risk	Bias in the presentation data: baseline characteristics by groups was not shown

Methods	Three‐group parallel RCT, 1 centre ITT: no  Overall study quality: high risk of bias Unit of randomization: participants Follow‐up period: 12 h Diagnosis of AMS "Headache and one additional sign or symptom were required for entering the trial" Scales used for assessing acute mountain sickness Clinical score (Appendix 8) AMS‐C score of the questionnaire (Appendix 8)
Participants	Number of participants randomized: 64 Sex: men = 49 (77%) Age : mean 31 years (range 18 to 52) Baseline data Clinical score mean: Intervention group — 4.1, 95% CI 3.7 to 4.5; Control group 1 — 4.3, 95% CI 3.7 to 4.8; Control group 2 — 4.5, 95% CI 4.0 to 5.0 AMS‐C score mean: Intervention group — 1.8, 95% CI 1.5 to 2.2; Control group 1 — 1.6, 95% CI 1.2 to 1.9; Control group 2 — 1.4, 95% CI 0.7 to 2.6 Inclusion criteria Mountaineers planning to stay overnight "who had ascended by foot and who stayed at 4559 m for at least 12 hours after treatment were eligible to enter the trial if they suffered from headache and one or more additional symptoms of acute mountain sickness". "Headache and one additional sign or symptom were required for entering the trial" Exclusion criteria "Subjects with clinical signs of high altitude pulmonary oedema (dyspnoea at rest, respiration rate > 25/min, and rales) and those who had taken acetazolamide or nifedipine during ascent"
Interventions	Intervention group (n = 31) Hyperbaric chamber at a pressure of 193 mbar; dose: 193 mbar; frequency: once during the trial; duration of the intervention: 1 h Control group 1 (n = 23) Hyperbaric chamber at a pressure of 20 mbar; dose: 20 mbar; frequency: once during the trial; duration of the intervention: 1 h Control group 2 (n = 10) Name: bed rest; dose: NA; frequency: once during the trial; duration of the intervention: Cointervention Analgesic: paracetamol (intervention group = 18; control group 1 = 15; control group 2 = 8), Antiemetic: thiethylperazine (intervention group = 2; control group 1 = 6; control group 2 = 2) **Characteristics of the chamber: fabric hyperbaric chamber made by Certec (F‐692 10 Sourcieux‐les‐Mines, France)
Outcomes	Do the authors define outcomes as 'primary' or 'secondary'?: yes Primary Symptoms of acute mountain sickness before, immediately after, and 12 h after treatment Permitted intake of analgesic Antiemetic drugs in the follow‐up period Secondary Arterial oxygen saturation Outcomes of interest in the review Reduction in illness severity scores of AMS
Notes	Country: Swiss‒Italian border, Capanna "Regina Margherita" in the Alps Valais Altitude setting 4559 m (barometric pressure 430 mmHg to 440 mmHg) Identifier number: not reported Study dates: 1990 to 1991 A priori sample estimation: no Conflicts of Interest: not reported Funding/Support "This study was supported by a grant from the research institute of the Swiss School of Sports, Magglingen, and by grant 3200‐0092.85 from the Swiss National Science Foundation"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomisation was performed in blocks of six (in 1990) and nine (in 1991)." Page 1098
Allocation concealment (selection bias)	High risk	Quote: "the investigator assigned the treatment by drawing a lot from an envelope containing the assignments of one block. When the remaining lots could be predicted they were added to the envelope containing the next randomisation block." Page 1099
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding method reported. Hyperbaric chamber compared to bed rest has not been masked. Outcomes are dependent on subjective assessment
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No blinding method reported; however, hyperbaric chamber compared to bed rest has not been masked and the outcome is dependent on subjective assessment
Incomplete outcome data (attrition bias)   All outcomes	High risk	Quote: "in 1990 the first seven subjects assigned to low pressure were unintentionally treated with 39 mbar (equivalent to a descent of 500 m) until the inaccuracy of the built in manometer in the low pressure range was discovered. Their results were excluded from analysis, although they were not significantly different from those obtained in subjects treated with 16 or 23 mbar." Page 1099. Outcome data was not available for seven participants in the intervention group (unbalanced attrition)
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Protocol not available
Other bias	Unclear risk	The use of analgesics and antiemetics was permitted during the study period as an option in the three groups. Authors found no significant statistical difference among groups in the use of these drugs

Methods	Two‐group parallel RCT, 1 centre ITT: no  Overall study quality: high risk of bias Unit of randomization: patients Follow‐up period: unclear, apparently 12 to 16 h Diagnosis of AMS 3 or more points in a symptoms severity score Scale used for assessing Acute Mountain Sickness The name of the scale is not reported. Authors described "The presence of the symptoms listed was scored as follows: one point for mild headache, nausea, dizziness, shortness of breath and insomnia and two points for severe headache (not relieved by paracetamol 500 mg) and for vomiting. Responses were checked with one of the investigators. Subjects then underwent a clinical examination for tachypnoea (two points), facial or peripheral oedema (one location one point, two or more locations two points), ataxia (heel to toe walking test and Romberg test two points), and pulmonary rales (discreet one point, pronounced two points). Patients with three or more points were selected for the drug trial"
Participants	Number of participants randomized: 35 Sex: men = 28 (80%) Age: "the two groups were comparable in age" Baseline data (mean symptom score per group) Dexamethasone group = mean 5.4 (SD = 1.7) Placebo group = mean 4.8 (SD = 1.0) Inclusion criteria Climbers with symptoms of acute mountain sickness (AMS: 3 or more points in the in the symptoms severity score) Exclusion criteria Frank high altitude pulmonary or cerebral oedema, or both
Interventions	Intervention group 1 (n = 17) Dexamethasone, route: by mouth; dose: "8 mg initially and another 4 mg after six and 12 hours"; frequency: initially and then every 6 h; duration of the intervention: 12 to 16 h Control group (n = 18) Identical placebo, route: not clearly reported, "identical placebo"; dose: not clearly reported, "identical placebo"; frequency: not clearly reported, "identical placebo"; duration of the intervention: 12 to 16 h Cointervention None reported
Outcomes	Not pre‐fixed as 'primary' or 'secondary' Acute mountain sickness score: baseline and after 12 to 16 h of intervention Number of patients becoming totally asymptomatic Arterial oxygen saturation Spirometric measurements: resting minute ventilation, forced vital capacity, and forced expiratory volume in 1 second Physiological measures: weight, pulse rate, blood pressure, arterial oxygen saturation Retinal photography Outcomes of interest in the review Complete relief of AMS symptoms Reduction in illness severity scores of AMS
Notes	Country: Swiss‒Italian border, Capanna "Regina Margherita" in the Alps Valais Altitude setting: 4559 m (barometric pressure 430 mmHg to 440 mmHg) Identifier number: not reported Study dates: not reported Priori sample estimation: no Conflicts of Interest: not reported. Funding/Support "This study was supported by a grant from the EMDO Stiftung" (University of Zurich)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "patients were randomly assigned". Page 1381
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "patients were randomly assigned". Page 1381
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "A double blind, randomised, placebo controlled trial". Page 1380
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "A double blind, randomised, placebo controlled trial". Page 1380
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All outcomes: no withdrawals. Outcome data was available for all participants
Selective reporting (reporting bias)	High risk	Protocol not available. Data presented graphically for individuals. No data available for each group for symptomatic scores
Other bias	Unclear risk	Baseline characteristics poorly presented

Methods	Results presented here correspond to the second of three experiments carried out by the researchers Experiment 1* Corresponds to an expedition 1 "a preliminary experiment comparing the effect of acetazolamide with methazolamide on blood gases was done in ten subjects" (acute mountain sickness was not an inclusion criteria) Experiment 2 Corresponds to an expedition 2 "A placebo‐controlled trial of acetazolamide for AMS was done in 13 subjects" Experiment 3 Corresponds to an expedition 3 "randomised double blind comparison of methazolamide and dexamethasone. Data from the dexamethasone arm of the trial were insufficient and have been omitted" Two‐group parallel RCT, 1 centre ITT: yes  Overall study quality: high risk of bias Unit of randomization: participants Follow‐up period: five days Diagnosis of AMS "Headache, anorexia/nausea and insomnia were scored; 1 = mild, 2 = moderate and 3 = severe. A score of 3 was given for any degree of ataxia, confusion or disorientation. For entry into the acute therapy trial on these expeditions, a persistent AMS score of 3 determined at clinical interview was required" Scale used for assessing Acute Mountain Sickness Self administered questionnaire of 18 questions (0: not present, 5: extreme) and a maximum score of 180
Participants	Number of participants randomized: 13 Sex: not reported for experiment 2 Age: not reported for experiment 2. They reported subjects aged 22 to 58 for the three experiments (see methods above) Baseline data Self‐administered AMS questionnaires Placebo: 21.6 (+/‐ 11) Acetazolamide: 33.3 (+/‐ 13.7) Inclusion criteria Healthy; non obese; unacclimatized subjects; persistent AMS score of 3 Exclusion criteria Not reported
Interventions	Intervention group (n = 6) Acetazolamide; route: oral; dose: 20 mg Kg^‐1 (1 to 1.5 grams) initially and then 500 mg daily Control group (n = 7) Placebo: "all drugs and placebo were prepared in identical gelatin capsules" Co‐intervention None reported
Outcomes	Not pre‐fixed as 'primary' or 'secondary' Headache worsening (proportion of participants per group) Response to acute therapy: using self‐administered AMS questionnaires of 18 questions scored 0 (not present) to 5 (extreme) (mean, SD and proportion with improvement) Blood gases Cerebral blood flow after allocation, before the administration of study drug and 20 h to 24 h later Outcomes of interest in the review Reduction in illness severity scores of AMS
Notes	Country: Karakoram mountains, located in the borders between Pakistan, India and China Altitude setting: 3200 to 5486 m Identifier number: not reported Study dates: not reported A priori sample estimation: no Conflicts of Interest: not reported Funding/Support "The work was supported by grants from the Arthur Thomson and the Wellcome Trusts." "Lederle Laboratories UK kindly supplied the acetazolamide"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "subjects were randomly allocated on a double‐blind basis" Page 51
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk' Quote: "subjects were randomly allocated on a double‐blind basis" Page 51
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "all drugs and placebo were prepared in identical gelatin capsules" Page 51 However, blinding was discontinued "Six of the placebo group were given 1.5 grams oral acetazolamide 24 hours after entry into the trial because AMS symptoms had persisted. At this point all subjects were aware of their treatment status" Page 51
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: "all drugs and placebo were prepared in identical gelatin capsules" Page 51 However, blinding was discontinued "Six of the placebo group were given 1.5 grams oral acetazolamide 24 hours after entry into the trial because AMS symptoms had persisted. At this point all subjects were aware of their treatment status" Page 51
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All outcomes: no withdrawals. Outcome data was available for all participants
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk'. Protocol not available
Other bias	High risk	Some participants in experiment 2 could have participated in the other two experiments (see methods above). Quote: "23 were studied during one of the three expeditions, six in two expeditions and three subjects in all three expeditions." Page 50. There is not enough information regarding how many participants from the second expedition were involved in the other two, and how much time passed between one expedition and another to identify a carry‐over effect. There was no statement considering the independence of authors with respect to those providing funding (source of industry bias)

Study	Reason for exclusion
Anand 1998	Cross‐over trial. The study design was considered inappropriate to the review question
Bates 2007	It is not a randomized trial
Benedetti 2015	Study intervention used for the prevention of HAI
Bradwell 1988	It is not a randomized trial
Broome 1994	Cross‐over trial. The study design was considered inappropriate to the review question: outcomes were reported after the patients received both intervention and control treatment
Brown 1977	Study intervention used for the prevention of HAI
Burtscher 1995	Cross‐over trial. The study design was considered inappropriate to the review question.
Bärtsch 1992	Narrative review
Bärtsch 1994	It is not a randomized trial
Deshwal 2012	It is not a randomized trial
Fagenholz 2007	It is a case series study
Forster 1982	Study intervention used for the prevention of HAI
Forwand 1968	Study intervention used for the prevention of HAI
Levine 1989	Cross‐over trial. The study design was considered inappropriate to the review question: outcomes were reported after the patients received both intervention and control treatment
Li 2010	Quasi‐randomized study (randomization was based on the participants’ hospitalization registration number)
Maggiorini 1995	Narrative review
Meehan 1986	The study population were healthy male volunteers
Oelz 1989	It is not a randomized trial
Oelz 1992	It is not a randomized trial
Roggla 2001	Study intervention used for studying AMS pathophysiology
Wright 1988	We wrote to info@bmres.co.uk in 2014 in order to contact the main author: Dr Wright (a.wright@bmres.org.uk) replied saying that the study was not randomized
Yan 2010	Quasi‐randomized study (randomization was based on the participants’ hospitalization registration number)
Yanamandra 2016	Quasi‐randomized study (randomization was based on the participants’ first name's starting initial)
Zhang 2012	The study Intervention does not meet the review eligibility criteria (Bundle treatment)

Trial name or title	Oral trimetazidine for reducing the symptoms of acute mountain sickness and improving exercise performance
Methods	Single centre randomized, parallel, double‐blind, controlled, prospective trial
Participants	Shapingba District and Tibetan Autonomous Prefecture of Garzê (Chongqing, and Sichuan), China Inclusion criteria Aged between 18 and 35 years, including 18 and 35 years People acutely ascending to high altitude. The gender ratio depends on actual situation There is no history of plateau for a long time exposure Before assessment, all subjects must be voluntary and sign a written informed consent Exclusion criteria The recent history of taking acute mountain sickness prevention drugs Engaged in specialized sports training Subjects with bad compliance The recent history of upper respiratory tract infection Subjects cannot take the drugs in our trial because of allergic history or other reasons Subjects with psychological or neurological disorder, and other conditions which are not appropriate for our trial
Interventions	Interventions Oral trimetazidine, 20 mg three times a day (20 participants) Control Oral placebo, the same dosage as oral trimetazidine (20 participants)
Outcomes	Lake Louise Score
Starting date	According to the Chinese Clinical Trial Registry, the study is currently recruiting (last update February 2016); however the reported study completion time is from 30 June 2013 to 30 December 2013
Contact information	Qin Jun; Huang Lan qinjunxq@126.com; huanglan260@yahoo.com.cn
Notes	Approved by ethic committee: yes. Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China Primary sponsor: Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China We have contacted the study leader, and the applicant by e‐mail in order to obtain more information (February 2017); answer is pending.

Trial name or title	Comparison of metoclopramide and ibuprofen for the treatment of acute mountain sickness
Methods	Allocation: randomized Endpoint classification: efficacy study Intervention model: parallel assignment Primary purpose: treatment Masking: double blind (subject, caregiver, investigator)
Participants	Trekkers travelling through the Annapurna Circuit in Nepal during the 3‐month time period of March to May 2012 Acute mountain sickness/high altitude headache Age group: adult/senior Sex: male and female Enrolment: 300 Inclusion criteria Presence at Manang recruitment centre (at approximately 11,500 ft) during the dates March through May 2012. Recent increase in altitude of >1000 ft vertical in last 24 h Presence of headache and at least one other symptom required for diagnosis of acute mountain sickness (including nausea, vomiting, fatigue, weakness, dizziness, lightheadedness or poor sleeping) Exclusion criteria Age less than 19 years old Known allergy or contraindication to either ibuprofen or metoclopramide Evidence of severe high altitude illness (e.g. High altitude pulmonary oedema (HAPE) as evidenced by dyspnoea at rest; or of High altitude cerebral oedema (HACE) as evidenced by altered mental status or ataxia) Known or suspected pregnancy Use of other analgesic or antiemetic within 8 h of study enrolment History of migraines or other chronic headache disorders Inability to provide informed consent
Interventions	Drug: ibuprofen "150 subjects with acute mountain sickness will be randomly assigned to take ibuprofen"; "Ibuprofen 400 mg tablet. Take one dose by mouth" Drug: metoclopramide "150 subjects with acute mountain sickness will be randomly assigned to take metoclopramide"; "Metoclopramide 10 mg tablet. Take one tablet by mouth"
Outcomes	Headache and nausea (visual analogue scales) Quote: "subjects will complete 100 mm visual analogue scales of both headache and nausea at time zero, 30, 60, and 120 minutes after taking the study medication. Visual analogue scales are a valid assessment of symptom severity for acute mountain sickness" Lake Louise acute mountain sickness Score Quote: "subjects will take the Lake Louise Acute Mountains Sickness score before taking the medication and 120 minutes after taking the medication. The Lake Louise Acute Mountain Sickness Score is a standard measure of the severity of acute mountain sickness and is commonly used in studies involving acute mountain sickness"
Starting date	March 2012 Currently recruiting, according to ClinicalTrials.gov registry (last verified February 2017) Estimated study completion date: March 2017
Contact information	John B Tanner, MD JBTANNER@PARTNERS.ORG Principal Investigator: Norman S Harris, MD, MFA Massachusetts General Hospital
Notes	International study Sponsor/collaborators: Massachusetts General Hospital URL: ClinicalTrials.gov/show/NCT01522326

PERMALINK

Interventions for treating acute high altitude illness

Daniel Simancas‐Racines

Ingrid Arevalo‐Rodriguez

Dimelza Osorio

Juan VA Franco

Yihan Xu

Ricardo Hidalgo

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

High altitude illness (HAI)

Acute mountain sickness (AMS) and high altitude cerebral oedema (HACE)

High altitude pulmonary oedema (HAPE)

Epidemiology of acute high altitude illness (HAI)

Description of the intervention

A) Non‐pharmacological interventions

B) Pharmacological interventions

How the intervention might work

A) Acute mountain sickness (AMS) and high altitude cerebral oedema (HACE)

B) High altitude pulmonary oedema (HAPE)

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Interventions

A) Non‐pharmacological interventions

B) Pharmacological interventions

Comparisons

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables and GRADE

Summary of findings for the main comparison. Non‐pharmacological interventions for treating acute high altitude illness.

Summary of findings 2. Pharmacological interventions for treating acute high altitude illness.

Results

Description of studies

Results of the search

1.

Included studies

Study design

Participants

Setting

Interventions

Funding sources

Outcomes

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation